1-carboalkoxymethylene-2, 4b-dimethyldodecahydrophenanthrene ketones and process



United S Patmt (1O -1-CARBOALKOXYMETHYLENE-2;4b DIMETHYL-DODECAH'YDROPHENANTHRENE yKETONES 'AND PROCESS Glen E. Arth, *Granford,N:J., George I."Poos, Ambler,

Pa., and Lewis H. Sarett, Princeton, NJ.,-*assignors to Merck & '00.,Inc., :Rahway, NJ., 'a corporation .of NewtJersey Application Deceniber31, 1956 "Serial No. 631,487

Claims. (Cl. 260--340.9)

No Drawing.

This invention is concerned 'generallywi'thdimethylcyclopentanopolyhydrophenanthrene compounds and withprocesses for preparing them. More lparticularly, it relates to a novelprocess for preparing A' -3,11,20-triketopregnene starting withl-alkoxyethinyl-l hyidrory-Z-methallyl 2,4b dimethyl 4 keto1,2,3,4,4a,4b,5,'6,7,8,10, 1.0a-dodecahydrophenanthrene compoundsihavingin the 7-position a'ketal or other substituent convertible. to "keto byhydrolysis, to the individual steps in this process, and to theintermediate :compoun'ds thus obtained,

This application 'is a continuation-impart 'ofrour .co-

pending application Serial No. 310,133,..filed September E 17, 1952, nowabandoned.

The A -3,11,20 triketo-pregnene, whichtis valuable as i an intermediatein the preparation of steroid hormones such as cortisone, may bechemically represented as follows:

ir/1* OZQU whereinR is alkyl, and X may be 1 Y- L I L 0 r I Y, and Ybeing hydrocarbon radicals, L and M bing oxygen or sulfur, and Zlbeingalkylene. In 568C115 of the process operations .utilized by us inpreparing A -3,11,20-

, 2 iketals grouping, cyclic thioketals and cyclic hemithio- Tketals, ishydrolyzed and, at the same time, the double bond shifts from ring B toringA thus forminga a',B- unsaturated tketone. We ordinarily preferrtovutilize an iethylene-dioxy substituentras the protecting group, and ourpreferred starting material is therefore l-alkoxyethinyl 1 hydroxy 2methallyl 2,4b dimethyl 4- :keto 7 ethylenedioxyv1,2,3,4,4a,4b,5,6,7,8,10,10a-

i dodecahydrophenanthrene.

Utilizing the latter compound as starting material, and .in accordancewith our presently invented process, L1- ialkoxyethinyl l hydroxy 2methallyl- 2,4b dimethyl --4 keto 7 ethylenedioxy -1l,-2,3,4,4a,4b,5,'6,I 7,8,10,10a-dodecahydrophenanthrene (Compound 1 hereinbelow) is reactedwith a dilute 'aqueous rnii neral acid solution to produce thecorresponding l-carboalkoxymethylene 2 methallyl 2,4b dimethyl 4 keto 7-ethylene-dioxy 1,2,3,4,4a,4b,5,6,7,8,10,109. dodecahydrophenanthrene(Compound 2); the latter compound is reacted with amalkaline saponifyingagent thereby forming 1 carboxymethylene 2 methallyl 2,4b dimeth-,yl---4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene (Compound 3). The 1- carboxyme'thylene 2methallyl 2,4b dimethyl 4- keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenezis then reacted withan alkali metalina'lower alkanol or in liquid ammonia to produce1--carboxymethyl 2 methallyl 2,4b dimethyl 4- hydroxy 7 -:ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene (Compound 4).Alternatively, this reduction operation, which involves the reduction ofbothwthe C-4 keto group to hydroxy and the l-carboxymethylene radical toa carboxymethyl grouping, can be carried'out step-wise by reacting the.l-carboxymethyl- 5 ene 2 methallyl 2,4b dimethyl 4 keto 7 ethylsenedioxy1,2,3-,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene with an 'alkalimetal borohydride or alkaline earth metal borohydridedo, form thecorresponding 1- the corresponding 1-carboalkoXymethyl-2-methallyl-2,4b-

carboxymethylene 2 -rmethallyl 2,4b dimethyl 4- 1140 hydroxy 7ethylene'dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-

dodecahydrophenanthrene (Compound 5 the latter compound is reacted Withan alkali metal in a lower alkanol or in liquid ammonia to producel-carboxymethyl-Z- methallyl 2,4b dimethyl 4 hydroxy 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene (Compound 4). Thiscompound is reacted with an esterifying agent, preferably an alkyliodide in the presence of a base and/or a diazoalkane to produce thecorresponding 1-carboalkoxymethyl-Z-methallyl-Z,4b-dimethyl 4 hydroxy 7ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,lOa-dodecahydrophenanthrene(Compound 6). This compound is reacted with an oxidizing agent,preferably under alkaline conditions, thereby forming the corresponding1-carboalkoXymethyl-2-methallyl-2,4b-dimethyl 4 keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7, '8;10;10wdodecahydrophenanthrene (Compound 7);alternatively, ,1-carboxymethyl-2-methallyl-2,4b-dimethyl-4-hydroxy -I7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-

dodecahydrophenanthrene can be reacted with an oxidizing agent to.produce 1-carboxymethyLZ-methallyl-Z,4bdimethyl 4 keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6, 7,8,10,10a --dodecahydrophenanthrene (Compound 8),which is then reacted with an esterifying agent to form dimethyl 4--'keto- '7 ethylenedioxy 1,2,3,4,4a,4b,5,

6,7,8,10,10a-dodecahydrophenanthrene (Compound 7).

triketo-pregnene;the keto group in ring A is blocked-with a ketal'orcyclic ketal protecting "group; 'At any stage in the process, this ketogroup may be regenerated by acid hydrolysis whereby theke'tal'siibs'tituent, which includes the simple ketals, thioketals,hemithioketals, cyclic The latter compound istreacted with osmiumtetroxide to form the osmate ester of 1-carboalkoxymethyl-2-(beta,gamma-'dihydroxyisobutyl) 2,4b dimethyl 4 keto- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene (Compound 9), whichis reacted with an aqueous alcoholic solution of an alkali metal sulfiteor bisulfite to produce the corresponding l-carboalkoxymethyl-2(beta,gamma dihydroxy isobutyl) 2,4b-

dimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,la-dodecahydrophenanthrene compound (Compound theLearboalkoxymethyl-Z-(beta,ganm1a-dihydroxy -isobuty1) 2,4b dimethyl 4-'keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene is reacted with periodic acid to form thecorresponding 1-carboalkoxymethy1-2-acetonyl-2,4b-dimethy1- '4 keto 7-'e'thy1enedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene(Compound 11). Alternatively, the1-carboalkoxymethyl-2-methally1-2,4b-dimethyl-4- keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene (Compound 7) can bereacted with ozone followed by hydrolysis of the ozonide thereby formingdirectly the corresponding l-carboalkoxymethyl- 2 acetonyl 2,4b dimethyl4 keto 7 ethylenedioxy- 1;2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene (Compound 11). The latter compound is reacted,under 1y represented as follows:

4 substantially anhydrous conditions, with a strong alkali therebyforming A -3-ethylenedioxy-11,16,20-triketo-pregnene (Compound 12). TheA -3-ethy1enedioxy-11,16, ZO-triketo-pregnene is reacted with an organicsulfonyl halide thereby forming the corresponding sulfonate ester ofA5116 3 ethylenedioxy 11,20 diketo 16 hydroxy-pregnadiene (Compound 13),which is reacted with hydrogen in the presence of a hydrogenationcatalyst to produce A 3 ethylenedioxy 11,20 diketopregnene (Compound14). The A -3-ethy1enedioxy-11, -diketo-pregnene is then reacted with anaqueous mineral acid solution whereupon the ethylenedioxy substituentattached to the 3-carbon atom is hydrolyzed and, at the sametime, thedouble bond shifts from ring B to ring A to form A-3,11,20-triketo-pregnene (Compound 15).

The reactions indicated herein above may be chemical- CH; CH] (3H3 JJ=GHv =CH3 C=UHg on, en, CH; o 0

=CEC-OR =C H.CO,OR =CHCO0H H 1 I 0 O 1 0 Compound 1 Compound 2 Compound3 1 J on, 0H. cm I =CH: =CH: =CHz Hg 5H1 AH; no H0 HO- I =CH-COOHCH;COOH -CH;COOR 0 F i [Q Compound 5 Compound 4 Compound 6 :CH, 5 011: VH Hg 0 0 CH;COOH CH;COOR/ Kg Compound 8 Compound 7 l GHQ-O J: CH OH CH:CH;- -O curb-0n =0 H; H3 H1 0 o o -CH C00R' CH,COOR' CH C00R' o 4 o 0 0Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 14wherein R and R are alkyl radicals and R" is an organic radical.

Although in the foregoing series of reactions, the substituent in ring Aof the polyhydrophenanthrene nucleus is shown as an ethylenedioxygrouping, instead of ethylenedioxy, any ketal substituent includingsimple ketals, thioketals, hemi-thioketals, cyclic ketals, cyclicthioketals, and cyclic hemi-thioketals can be used as the protectinggrouping. In place of a ketal substituent, an enol-ether may be used asthe protecting group, if desired. Accordingly, instead ofl-alkoxyethinyl-1-hydroXy-2-methallyl- 2,4b dimethyl 4 keto 7ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,l0,10a dodecahydrophenanthrene, any1- alkoxyethinyl-Z-(allyl or alkallyl)-2,4b-dimethyl-4-lceto--1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene compound, havingin the 7-position a ketal substituent (including simple ketals,thioketals, hemi-thioketals, cyclic ketals, cyclic thioketals, andcyclic hemi-thioketals) hydrolyzable to a 7-keto grouping, may be usedas starting material in the presently invented process. In each of theprocess operations utilized by us in preparing A3,11,20-triketo-pregnene, the keto group in ring A is blocked by a ketalprotecting group (as above defined). At any stage in the process, thisketo group may be regenerated by acid hydrolysis whereby the ketal groupis hydrolyzed and, at the same time, the double bond shifts from ring Bto ring A thus forming an one-unsaturated ketone. It is ordinarilypreferred to utilize an ethylenedioxy substituent as the protectinggroup, and our preferred starting material isl-alkoxyethinyl-l-hydroxy-Z- methallyl 2,4b dimethyl 4 keto 7ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,l0,la-dodecahydrophenanthrene.

This l-alkoxyethinyl-l-hydroxy 2 methallyl 2,4b-dimethyl-4-keto-7ethylenedioxy 1,2,3,4,4a,4b,5,6,7 ,8,l0, adodecahydrophenanthrene is anew compound which may be prepared according to the following procedure:

.p-ethoxy-propionaldehyde is reacted with ethyl magnesium bromide toproduce 1-ethoXy-3-hydroxy pentane which is reacted with chromic acidthereby oxidizing the .hydroxy substituent to form1-ethoXy-3-keto-pentane; the .latter compound is treated with ethylortho formate and :ethanol in the presence of hydrogen chloride toproduce 1,3,3-triethoxy-pentane which, upon reaction with hot potassiumbisulfate, is converted to 3-ethoxy-l,3-pentadiene. The3-ethoxy-l,3-pentadiene is reacted with benzoquinone in accordance withthe Diels-Alder condensation procedure to produceS-methyl-G-ethoxy-1,4,4a,5,8,8a-hexa- .hydronaphth-alenee1,4-dione whichis then reacted with Compound 15 1,4-diol which is reacted with-ahydrolyzing agent to produce 5-me'thyl-6-ketoperhydronaphthalene 1,4diol. The reactions indicated above are described in detail in aco-pending application of one of the present applicants, Serial No.216,109, filed March 16, 1951, now abandoned. The5-methyl-6-keto-perhydronaphthalene-1,4-diol is then reacted withN-(3-keto-butyl)-N,N-diethyl-N-methylammonium iodide in the presence ofpotassium hydroxide to produce7-keto-4b-me'thyl-l,2,3,4,4a,4b,5,6,7,9,10,1021-dodecahydrophenanthrene-1,4-diol; this reaction is described in detailin co-pending application, Serial No. 228,126, filed May 24, 1951, nowPatent No. 2,617,828. The7-keto-4b-methy1-1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-l,4-diolis reacted with ethylene glycol in ethylene dichloride solution and inthe presence of p-toluene 'sulfonic acid catalyst thereby forming1,4-dihydroxy-4b-methyl-7-ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a-dodecahydrophenanthrene. The1,4-'dihydrordy-4b-methyl-7-ethylenedioxy-1,2,,3,4,4a,4b*,;5,6,7,%8,l0,10a-dodecahydrophenanthrene is reacted with cyclohexanone and aluminumisopropoxide in benzene solution to produce the correspondingl-keto-4-hydroxy-4b-methy1- 7 ethylenedioxyl,2,-3,4,4a,,,41b-,5,6,7,8,10,10a dodecahydrophenanthrene. The reactionsindicated hereinabove are described in detail in a co-pendingapplication of the present applicants, Serial No. 286,808, filed May 8,1952, now abandoned.

The 1-keto-4-hydroxy-4b-methyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene is reacted with methyliodide in the presence of potassium tertiary butoxide in benzene therebyforming l-keto-'2,4bdimethyl-4-hydroxy-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7j8, 10,10a-dodecahydrophenanthrene; the lattercompound is reacted with chromium trioxide-pyridine complex to form1,4-diketo-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a',4b,5, 6,7,8, 1 0, l0a-dodecahydrophenanthrene. The methylation reaction indicatedhereinabove is described in detaillin a co-pending application in whichone of the present applicants is co-inventor Serial No. 306,488, filedAugust 26, 1952, now abandoned. The oxidation reaction indicatedhereinabove is described in detail in a co-pending application in whichone of the present applicants" is the "sole inventor, Serial No.2'92,985,-filed June 11,1952, W

abandoned. The1,4-diketo-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,5,6,7,8,10,Mar-dodecahydrophenanthreneis reacted with methallyl iodide in a tertiary butyl alcohol solution ofaluminum tertiary butylate, thereby forming 1,,4-diketo-2-methallyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene. The latter compound isreacted in ether-benzene solution with an alkoxy acetylene magnesiumbromide to produce the correspondingl-alkoxy-ethinyl-l-hydroxy-Z-methallyl-Z,4b-dimethyl-4-keto-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene.

Alternatively, the l-keto-2,4b-dimethyl-4-hydroxy-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene isreacted with methallyl iodide in a tertiary butyl alcohol solution ofaluminum tertiary butylate to produce 1-keto-2-methallyl-2,4bdimethyl-4-hydroxy-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene which, upon reaction with an alkoxy acetylenemagnesium bromide in ether-benzene solution, is converted to thecorresponding 1-alkoxyethinyl-1,4-dihydroxy-2-methallyl-2,4b-dimethyl-7ethylenedioxy-1,2,3,4, 4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene. Thereactions indicated hereinabove are described in detail in two copendingapplications of the present applicants, Serial No. 306,509, filed August26, 1952, now abandoned, and Serial No. 308,172, filed September 5,1952, now abandoned. Where it is desired to utilize another cyclic ketalor other ketal substituent (as defined above) or an enol-ethersubstituent to protect the 7-keto grouping, this is introduced in theforegoing procedure by reacting the intermediate1,4-dihydroxy-7-keto-4b-methyl-1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene under substantially anhydrous conditions and inthe presence of an acid catalyst, with a lower alkanol such as an excessamount of methanol, ethanol, propanol, butanol, and the like, or anexcess of another low molecular weight glycol such as propylene glycol,butylene glycol, or an excess of a thioglycol or dithioglycol such as,ethanedithiol, propane-1,2-dithiol, B-mercaptoethanol,

mercapto-propanol, and the like. If it is desired to use an enol-etheras the protecting group, the 1,4-dihydroxy- 7-keto-4b-methyl1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene is reacted, undersubstantially anhydrous conditions in the presence of an acid catalystwith an alkyl ortho formate.

The rearrangement of the l-alkoxyethinyl-l-hydroxy- 2 methallyl 2,4bdimethyl 4 keto 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene, its 2-allyl and 2-alkallyl homolog, and other7- ketals thereof, is carried out by bringing this compound intointimate contact with an aqueous mineral acid in solution in an organicsolvent for the compound, for example a cyclic ether such astetrahydrofuran, tetrahydropyran, dioxane or an alkanol such as ethanol,isopropanol, butanol and the like, under which conditions the ketal orenol ether substituent attached to the C-7-carbon atom is notappreciably hydrolyzed. We ordinarily utilize tetrahydrofuran as theorganic solvent in conjunction with 10% aqueous sulfuric acid solution,and allow the slightly exothermic reaction which takes place to proceedat a temperature of about 25-30 C. Under these conditions, the reactionis ordinarily complete in about three and one-half hours. In accordancewith this procedure, there is Obtained the desired1-carboalkoxymethylene-2methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy1,2,3, 4,4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene admixed with aby-product, l-carboalkoxymethyl-l-hydroxy-2 methyl 2,4b dimethyl 4 keto7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene.These two products can be conveniently isolated from the reactionmixture by neutralizing the mineral acid with a mildly aqueous alkalinesolution, preferably a saturated aqueous solution of sodium bicarbonate,distilling the organic solvent under reduced pressure, and extractingthe oil which separates during distillation into the ether.

After washing, drying and evaporating the ether extract, there isobtained a residual oily material from which it is possible tofractionally crystallize the foregoing components in substantially pureform. It is ordinarily preferred, however, to separate these twoproducts in pure form by chromatography on acid-washed alumina. This isaccomplished by dissolving the residual oily material inbenzene-petroleum ether, contacting this solution with acid-washedalumina and eluting the adsorbate with a mixture of petroleumether-ether. From the eluates richer in the petroleum ether component isobtained the 1 canboalkoxymethylene 2 methallyl 2,4b dimethyl 4 keto 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,lOa-dodecahydrophenanthrene andfrom the following fractions which contain a relatively higherproportion of ether is obtained the l-carboalkoxymethyl-l-hydroxy- 2methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene.

The saponification of the ester grouping in the l-carboalkoxymethylene 2methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene is conductedutilizing an alkaline hydrolyzing agent since the 7-position substituentis unstable under the conditions normally encountered in the acidhydrolysis of esters. The hydrolysis is conveniently carried oututilizing an aqueous methanolic solution containing potassium carbonateand a small amount of potassium hydroxide, but other alkalinehydrolyzing agents can be utilized if desired. When this preferredhydrolyzing agent is utilized, saponification may be carried out at roomtemperature, or more rapidly, if desired, by heating the reactants atthe reflux temperature of the solution. The methanol is evaporated underreduced pressure, and the aqueous mixture diluted with approximately anequal volume of water, whereupon the potassium salt of2-carboxymethylene-2-methallyl-2,4bdimethyl 4 keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6, 7,8,lO,IOa-dodecanhydrophenanthrene may precipitateas an oil. The aqueous solution or suspension is then extracted withether, and the aqueous mixture is acidified with a mildly acidic reagentsuch as sodium dihydrogen phosphate. The acidic material which separatesis extracted with chloroform, the chloroform extracts are dried andevaporated under reduced pressure to give 1- carboxymethylene 2methallyl 2,4b dimethyl 4 keto 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene. This material maybe further purified by washing with ether and recrystallizing thematerial from ethyl acetate.

As set forth herein above, the 1-carboxymethylene-2- methallyl 2,4bdimethyl 4 keto 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene can be converted directly to1-carboxymethyl-Z-rnethallyl- 2,4b dimethyl 4 hydroxy 7 ethylenedioxy1,2,3, 4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene by reaction withan alkali metal, such as sodium, lithium, or potassium, or this reactioncan be carried out in two operations, first reducting the 4-ketosubstituent to hydroxy utilizing an alkali metal borohydride such assodium borohydride, lithium borohydride, potassium borohydride or analkaline earth metal borohydride such as calcium borohydride, and thenreducing the l-carboxymethylene substituent utilizing the alkali metal.

The reaction between the 1-carboxymethylene-2-methallyl 2,4b dimethyl 4keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene and the alkali metalborohydride or alkaline earth metal borohydride is conducted bysuspending the hydrophenanthrene compound in water or in aqueous organicsolvent such as aqueous tetrahydrofuren, aqueous dioxane, aqueousalkanol, and the like, and adding the alkali metal or alkaline earthmetal borohydride cautiously to the mixture. After all the reducingagent has dissolved, the resulting mixture is allowed to standpreferably at a temperature between about room temperature and (3.,

9 although higher. and lower temperatures maybe used .if desired. Whenthe reaction is carried out at a temperature of about 30C., the reactionis ordinarily complete after a reaction time of about 24 hours. Theaqueous mixture is carefully acidified, preferably maintaining the pHabove about 3.5; it is preferred to utilize sodium dihydrogen phosphatefor this acidification. The product which precipitates is extracted withan organic solvent such as chloroform. The chloroform extracts arewashed, dried and evaporated in vacuo to give an oil which can becrystallized from ether to give crystalline l-carboxymethylene 2methallyl 2,4b dimethyl 4 hydroxy 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene.

The latter product or, if desired, the starting l-carboxymethylene 2methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy 71,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene is reacted with analkali metal such as metallic lithium, sodium or potassium, and thelike, in solution in a lower alkanol and/or in. liquid ammonia.

Where metallic lithium or'potassium are used as the reducing agents, itis preferred to use liquid ammonia. 'The reaction system which has beenfound most advantageous 1s potassium-liquid ammonia-isopropanol.

The reaction between the 1-carboxymethyleue-Z-methallyl-2,4b-dimethy1-4-(keto or hydroxy)-7-ethylenedioxy-1,2,-3,4,4a,5,6,7,8,l0,10a-dodecahydrophenanthrene and metallic lithium orpotassium is conveniently carried out by suspending thehydrophenanthrene compound in liquid ammonia and adding the alkali metalportion-wise to the suspension. If desired, a lower alkanol such asethanol, butanol, and the like may be added to the reac' tion mixture;although the reduction reaction will occur in the absenceof the alkanol,the yield of the desired product is improved, in some cases, by the useof the alkanol. The liquid ammonia reaction mixture is stirred at theboiling point of liquid ammonia until the ammonia has evaporated. Thecrude reaction mixture is treated with benzene, and if necessary, asmall amount of ethyl acetate or alcohol is added to destroy the excessalkali metal. The resulting mixture is then diluted with water, thebenzene layer is discarded, and the alkaline layer containing thereduction product is solidified. The

material which precipitates is extracted with chloroform,

and the chloroform extract is washed, dried and evaporated. .The oilymaterial thus obtained is crystallized by heating with ether to givecrude l-carboxymethyl-Z-methallyl-2,4b-dimethyl-4-hydroxy-7-ethylenedioxy 1,-

. 2,3 ,4,4a5,6,7,8, l 0, la-dodecahydrophenanthrene.

When sodium or potassium is used as the reducing agent, the reaction isconveniently carried out by bringing together thel-carboxymethylene-2-methallyl-2,4b-dimethyl-4-(keto or hydroxy)7-ethylenedioxy-l,2,3,4,4a,-

v 4b,5,6,7,8,10,10a-dodecahydrophenanthrene, alkali metal,

and a hot lower alkanol, and stirring the resulting mixture under refluxfor a period of about fifteen minutes. The reaction mixture isevaporated to about one-half Volume in vacuo, diluted with water and theaqueous solution is carefully acidified. The acidic aqueous mixture isextracted with chloroform, and the chloroform extract is dried andevaporated in vacuo. The residual material consists of crudel-carboxymethyl-Z-methallyl- 2,4b dimethyl 4 hydroxy 7 ethylenedioxy1,2,3,-

I 4,4a,5,6,7,8,l0,lOa-dodecahydrophenanthrene.

When the reduction is carried out utilizing as starting material the 1carboxymethylene 2 methallyl 2,4bdimethyl 4 keto 7 ethylenedioxyl,2,3,4,4a,5,6,7,- 8,10,10a dodecahydrophenanthrene, there may beobtained, in addition to the 1-carboxymethyl-Z-methallyl-2,4b-dimethyl-4-hydroxy-7ethylenedioxy-1,2,3,4,4a,4b,-5,-6,7,7,10,lOa-dodecahydrophenanthrene, a small amount of1-carboxymethyl-2-rnethallyl-2,4b-dimethyl-4-keto-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10a, dodecahydrophenanthrene.

Esterification of the '1-carboxymethyl-2,4b-dnnethyl-4- (hydroxy orketo) 7 ethylenedioxy 1,2,3',4,4a,4b,5 ;d,-.7,8,10,l0a-dodecahydrophenanthrene can be carried out by any of theusual methods of esterification but, in view of the ease of hydrolysisof the metal substituent in the 7-position, it is ordinarily preferredto conduct this esterification under alkaline conditions using adiazoalkane or an alkyl iodide in the presence of a base as theesterifying agent. The reaction utilizing a diazoalkane such asdiazomethane or diazoethane is conveniently carried out by dissolvingthe l-carboxymethyl-Z- methallyl-2,4b-dimethyl-4-(hydroxy orketo)-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene in an organic solvent such as ether and addingto this solution an excess of the diazoalkane in an inert organicsolvent medium such as ether. The resulting solution is allowed to standat approximately room temperature until the evolution of nitrogenceases, the solvents are evaporated, and the residual oil iscrystallized to give l-carboalkoxymethyl 2 methallyl 2,4b dimethyl 4(hydroxy or keto) 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene.

The 1-carboalkoxymethyl-2-methallyl-2,4b-dimethyl-4- hydroxy 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene can beconverted by reaction with an oxidizing agent to the corresponding4-keto derivative, which is'alternatively obtained by the esterificationof the 1-carboalkoxymethyl-Z-methyallyl-2,4b-dimethyl 4 keto 7ethylenedioxy 1,2,3,4,4a,5,6,7,8,- l0,10a-dodecahydrophenanthrene asdescribed hereinabove. As oxidizing agent for this reaction, weordinarily prefer to utilize chromium trioxide-pyridine complex,although other oxidizing agents such as chromic acid may be employed ifdesired. Using the preferred oxidant, the l carboalkoxymethyl 2methallyl 2,4bdimethyl 4 hydroxy 7 ethylenedioxy 1,2,3,4,4a,4b,-5,6,7,8,10,10a-dodecahydrophenanthrene is dissolved in pyridine andmixed with the complex formed by adding chromium trioxide to an excessof pyridine. The resulting mixture is allowed to stand at a temperaturewithin the range of about 0 C. to C. for a period of time, dependingupon the temperature; at room temperature, the reaction is ordinarilycomplete in about 15 hours. The reaction mixture is diluted with waterand the aqueous solution is extracted with a water-immiscible organicsolvent such as ether. The organic solvent extracts are washed withwater, dried, and the solvent evaporated. The residual oil iscrystallized to give 1- car-boalkoxymethyl 2 methallyl 2,4b dimethyl -4-keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-do- 'decahydrophenanthrene.

. grouping. This can be accomplished in a two-stop oxidation utilizingosmium tetroxide followed by periodic acid or in a'single-step utilizingozone. Where the osmium tetroxide procedure is used, the1-carboalkoxymethyl-2- methally 2,4b dimethyl 4 keto 7ethylenedioxyl,2,3,4,4a,4b,5,6,7,8;10,10a dodecahydrophenanthrene isdissolved in a dry ether benzene solution and approximately oneequivalent of osmium tetroxide is added to the solution. In a fewminutes the osmate ester of the l-carboalkoxymethyl 2 (beta, gammadihydroxy isobutyl)- 2,4b dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8, l0,10a-dodecahydrophenanthrene precipitates, andthe resulting mixture is allowed to stand at about room temperature fora period of about one hour. At the end of this period, the reaction issubstantially complete. An organic solvent for the osmate ester, forexample a lower alkanol such as ethanol, or a cyclic ether such astetrahydrofurane is added to the reaction mixture to dissolve the osmateester, and the latter is reacted With a mildly alkaline hydrolyzingagent under reducing conditions such as an aqueous solution of an alkalimetal sulfite or bisulfite. The osmium oxide which precipitates from theV hydrolysis is removed by filtration, and the filtered solution isevaporated under reduced pressure. The residual oily material thusobtained is shaken with a mixture of pound for example a lower alkanol,such as ethanol, and

a cyclic ether, such as tetrahydrofuran and the like, and to thissolution are added pyridine and an aqueous solution of periodic acid.The glycol cleavage which takes place is ordinarily complete in a fewminutes. The reaction mixture is diluted with water, and the aqueousreaction mixture is extracted with an organic solvent such as ether. Theorganic solvent extract is washed, dried,

and evaporated to give an oily product which can be crystallized to givesubstantially pure l-carboalkoxymethyl 2 acetonyl 2,4b dimethyl 4 keto 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene.

When the conversion of the 2-methallyl substituent to an acetonylradical is conducted utilizing ozone instead of osmium tetroxidefollowed by periodic acid, the l-carboalkoxymethyl 2 methallyl 2,4bdimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene is dissolved in a lower alkanol such asmethanol, the solution is cooled to a low temperature of about 80 C.,and ozonized oxygen containing one equivalent of ozone based on thehydrophenanthrene compound is passed through the solution. The resultingmixture is warmed to approximately C., and the ozonide product in thereaction mixture is decomposed under reductive conditions either bymeans of a small amount of zinc and aqueous acetic acid, orcatalytically by contacting the ozonide in an aqueous medium withhydrogen and a platinum catalyst. When the ozonide is reacted with zincand aqueous acetic acid, the reaction mixture is made slightly alkaline,filtered and the solvents evaporated therefrom in vacuo at a temperaturebelow about 20 C. The residual material is extracted with ether, theethereal solution is chromatographed on acid-Washed alumina and thealumina-adsorbate is eluted utilizing ether-petroleum ether. Uponevaporation of the ether-petroleum ether eluate, there is obtained 1carboalkoxymethyl 2 acetonyl 2,4b dimethyl 4 keto 7 ethylenedioxyl,2,3,4,4a,4b,5,6, 7,8,10,10a dodecahydrophenanthrene.

We then prepare a substantially anhydrous solution of 1carboalkoxymethyl 2 acetonyl 2,4b dimethyl 4 keto 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene in an aromatichydrocarbon such as benzene, toluene, and the like. This solution isbrought into contact with a solid anhydrous, strongly basic material,for example an alkali metal alkoxide, such as sodium methoxide,potassium t-butoxide, an alkali metal, such as metallic sodium, analkali metal hydride, such as sodium hydride, an alkali metal amide suchas sodamide, and the like. The resulting mixture is ordinarily stirredat a temperature within the range of about 20 to 50 C. althoughtemperatures somewhat below or above this range may be used, if desired.When the reaction is carried out at about room temperature, thecyclization is substantially complete in approximately ten hours. Thereaction mixture is poured into water and immediately acidified with anexcess of a mildly acidic reagent such as an aqueous solution of primarysodium phosphate. The acidified solution is extracted with an organicsolvent such as chloroform and the solvent extract dried, filtered andevaporated to give crystalline A 3 ethylenedioxy 11,16,20 triketopregnene,

12 which can be further purified if desired by recrystallization. Acidhydrolysis of the A 3 ethylenedioxy 11, 16,20 triketo pregnene gives A3,11,16,20 tetraketo pregnene.

The A 3 ethylenedioxy 11,16,20 triketo pregnene is then reacted with anorganic sulfonyl chloride, preferably p-toluene sulfonyl chloride. Thisreaction is carried out dissolving the pregnene compound in a tertiaryamine such as pyridine and adding the organic sulfonyl chloride to theresulting solution. The reaction is allowed to proceed at about roomtemperature under which conditions the reaction is ordinarily completein about twelve to twenty-four hours. The excess organic sulfonylchloride and pyridine are neutralized by the addition of a mildlyalkaline aqueous solution such as aqueous sodium bicarbonate, and theresulting mixture is agitated for a short period of time, during whichtime the sulfonate crystallizes. An organic solvent such as benzene isadded to the reaction mixture, the mixture is poured into ice water, andthe organic layer is separated. The organic layer is washed with water,dried and evaporated in vacuo. The residual material can be purified byrecrystallization to give the 16-sulfonate ester of A -3-ethylenedioxy-16-hydroxy 11,20 diketo pregnadiene in substantially pureform.

The catalytic hydrogenation of the latter material is convenientlycarried out by dissolving the l6-sulfonate ester of 13 3 ethylenedioxy16 hydroxy 11,20 diketo-pregnadiene in benzene, adding a hydrogenationcatalyst, such as palladium on barium carbonate, and contacting themixture with hydrogen at atmospheric pressure, or preferably atsuperatmospheric pressure. When the hydrogenation reaction is carriedout at room temperature and at a pressure of about forty pounds persquare inch, the reaction is substantially complete in about twentyhours. It is ordinarily preferred to add additional amounts of catalystduring the course of the hydrogenation. The hydrogenation mixture isfiltered, and the filtered solution is evaporated in vacuo. The residualoil is crystallized to give substantially pure A 3 ethylenedioxy 11,20diketo pregnene.

The latter compound is treated with a hydrolyzing agent, preferably anaqueous mineral acid such as hydrochloric acid, perchloric acid,p-toluene sulfonic acid, and the like, thereby hydrolyzing the ketalsubstituent in the 3-position of the molecule. When aqueous perchloricacid is employed, the hydrolysis is conveniently carried out bydissolving the A 3 ethylenedioxy 11,20 di keto pregnene in an organicsolvent such as tetrahydrofuran, adding a dilute aqueous solution ofperchloric acid to the resulting solution, and allowing the resultingmixture to stand at about room temperature for a period of about threeto four hours. The solvents are evaporated in vacuo, and the residualmaterial is extracted with an organic solvent such as chloroform. Thechloroform extract is dried, the chloroform evaporated in vacuo, and theresidual material is crystallized to give substantially pure A 3,11,20triketo pregnene.

The stereoisomeric form of A -3,11,20-triketo-pregnene having a meltingpoint of about 176 C. possesses the stereoisomeric configurationcharacteristic of the naturally-occurrin steroid hormones such asprogesterone. We refer to this stereoisomer by the name of ll-ketoprogesterone. This compound is obtained in the form of a racemic mixtureof the dand l-forms, and is referred to more specifically asdl-ll-keto-progesterone.

The 3-ethylenedioxy derivative of dl-A -3,11,20-triketopregnene ofmelting point 175-176 C. obtained as hereinabove described may beconverted to the therapeutically active material3,11,20-triketo-l7a-hydroxy-2l-acetoxy- A -pregnene as follows:dl-3-ethylenedioxy-11,20-diketo- A -pregnene is treated with dimethyloxalate and then with alkali to form the 0-21 oxalyl acid derivative. Onformation of the strychnine salts of the components of this racemicmix-ture the d-salt precipitates and may be 13 recovered by filtration.Decomposition of this" strychnine salt andihydrolysis' of the C21oxalyl'acid group yields 3-ethylenedioxy-11,20-diketo-A pregnene identical with"that obtained from naturally occurring materials.

'Iodination under alkaline conditions of the natural isomen of the'21-oxalyl acid of 3-ethylenedioxy-11,20-diketo- A -pregnene, "which maybe obtained in the above described-resolution procedure, yields3-ethylenedioxy-11, 20-diketo-21-iodo-A -pregnene. By treatment 'of thislatter compound with potassium acetate there is obtained 3-"ethylenedioxy-l1,20 diketo-21-acetoxy A pregnene ofmelting"point"193.5-194 C.

Reaction of the last mentioned compound with hydrogen-cyanide followedby dehydration of the C-20 cyan- "hydrin thusformed with phosphorousoxychloride yields -3 ethylenedioxy 11 keto 20 cyano 21 acetoxy "b-pregnadiene, which maybe oxidized with potassium permanganate to 3ethylenedioxy 11,20 diketo 17cc rhydroxy 21 acetoxy A pregnene. 3,11,20triketo 17a -"hyd.roxy 21 acetoxy A pregnene, alternatively known ascortisone acetate, may be prepared by acid hydrolysis of the abovementioned 3-ethylenedioxy-11,20- "diketo 17 a-hydroxy-2l-acetoxy-Apregnene.

,"The 3-ethylenedioxy-derivative of dl-3,11,20-triketo-A "pregnene mayalso'be converted into dl3,11,20-triketo' i Toa solution of 24- g. of1-ethoxyethinyl-Z-methallyl-Z, 4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a -dodecahydrophenanthrene-1-ol-4-one (M.P. 133-134 C.) in160ml. of tetrahydrofuran was added ml. of 10% aqueous sulfuric acid.Theresulting mixture was maintained at a temperature within the range of27 C. to 29 C. for a period of about three and one-half hours. *At theend of this time, an excess of a saturated aqueous 'solution of sodiumbicarbonate was addedto the reac- "tion mixture, and the tetrahydrofuranwas evaporated "from the aqueous-mixture underreduced pressure. The'oilwhichseparated was extracted into ether; the ether extract waswashed once with water, dried over sodium "sulfate, and the etherwasevaporated. The residual oily materialwas dissolved in ether andchromatographed on acid-washed alumina. The'adsorbate was eluted withmixtures of ether andpetroleum' ether; upon evaporation of the:8i2petroleum ether-ether eluate there was obtained'1-carboethoxymethylene-2-methallyl-2,4b-dimethyl- 7 ethylenedioxy1,2-,3,4 ,4a,4b,5,6,7,8,10,10a dode- ..cahydrophenanthrene-4-one; uponevaporation of the 7:3 petroleum ether-ethereluate there was obtainedl-carbo- :ethoxymethyl 2 methallyl 2,4b dimethyl 7 ethyl enedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro phenanthrene 1 01 4 -.onehaving an M.P. of 99- 101 C.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of1-ethoxyethinyl-2-methallyl-2,4b-dimethyl-7-ethylenedioxy1,2,3;4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one havingan M.P. of 133134 0., there was obtained the stereoisomer ofl-carboethoxymethyl-Z- methallyl 2,4b -'dimethyl 7 ethylenedioxy1,2,3,4,

. one-half hours.

14 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1 -'ol- 4-one having anM.P. of 99-101 C. and the stereoisomer of 1 carboethoxymethylene -2methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one having an M.P.of. 133- 134 C. and 151-152 C. (dimorphic).

By using a stereochemical modification of theabove 1 ethoxyethinyl 2methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenantnrene-l-ol-4-one starting material having an M.P. of131-132 C. there was obtained the stereoisomer of 1 carboethoxymethyl 2methallyl 2,4b dimethyl- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 1 ol 4 one having an M.P. of 146 C. and thestereoisomer of l-carboethyxymethylene- 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4one having an M.P. of 9496 C.

Example 2 A suspension of 4.1 g. of l-carboethoxymethylene-2-..rnethallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,

4a,5,6,7,8,10,l0a dodecahydrophenanthrene 4 one in 50 ml. of methanoland 50 ml. of water containing 10 g. of potassium carbonate and l g. ofpotassium hydroxide was heated to boiling under reflux for a period oftwo and At the end of this time, all of. the ester had dissolved. Themethanol was evaporated under reduced pressure, whereupon the potassiumsalt of l-carboxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro- .phenanthrene-4-one separatedas an oil, and approximate- .ly 50. ml.of water was added to dissolvethe salt.

The aqueous mixture was extracted once with ether, and then acidifiedwith excess sodium dihydrogen phosphate. The acidified mixture was thenextracted with chloroform, and the chloroform extract was dried oversodium sulfate, filtered and evaporated to dryness under reducedpressure at a bath temperature which did not exceed about 40 C. Theresidual crystalline material was washed with ether and recrystallizedfrom ethyl acetate to give substantially pure 1 carboxymethylene 2methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a'dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 carboethoxymethylene 2 methallyl2,4b dimethyl 7 ethylene-dioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4 one having an M.P.of 133- 134 C.; 151.2 C., there was obtained the stereoisomer of lcarboxymethylene 2 methallyl 2,4b dimethyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having anM.P. of 223-225" C.

When the stereoisomer of l-carboethoxymethylene-Z- methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 one having an M.P. of 9496 C. was used asstarting material and the saponification conducted as described in thefirst paragraph of the present example except that the potassiumhydroxide was omitted from the saponification mixture, there wasobtained the stereoisomer of l-carboxymethylene 2 methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a4b,5,6,7,8,10,10adodecahydrophenanthnene-4-one having an M.P. of 203-205 C.

A solution containing about 50 mg. of l-carboxymethylene 2 methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4b,5,6,7,8,10,10adodecahydrophen-anthrene-4-one and about 15 mg. of p-toluene sulfonicacid in about 3 m1. of acetone was heated under reflux for a period ofapproximately twenty minutes. The acetone reaction mixture was dilutedwith water and the resulting aqueous mixture was extracted withchloroform. The chloroform extract was dried and evaporated to'drynessto give 1-carboxymethylene-2-methallyl-2,4b-dimethyl 1,

I pound).

2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene 4,

7-dione.

Example 3 A solution of 100 mg. of 1-carboxymethylene-Z-methallyl 2,4bdimethyl 7 ethylenedioxy l,2,3,4,4a,4b, 5,6,7,8,l0,10adodecahydrophenanthrene 4 one was suspended in ml. of water. One gram ofsodium borohydride was added cautiously until the initial reaction wascompleted. After all of the reducing agent had dissolved, the mixturewas heated at 100 C. for three hours. The reaction mixture was cooled,acidified with sodium dihydrogen phosphate, and the acidified mixtureextracted with chloroform. The chloroform extract was washed with water,dried over anhydrous sodium sulfate, and filtered, and the chloroformwas evaporated from the filtered solution in vacuo at a bath temperatureof less than about 40 C. The residual oil was crystallized from ether,and recrystallized from ethyl acetate to give substantially pure 1carboxymethylene 2 methallyl 2,4b dimethyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol.

In accordance with the foregoing procedure and utilizing as startingmaterial the stereoisomer of l-carboxymethylene 2 methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one having an M.P. of 223225 C. there wasobtained the stereoisomer of 1-carboxymethylene-2-methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10adodecahydrophenanthrene 4 01 having an M.P. of 211214 C.

Upon heating, under reflux, a solution of 50 mg. of 1carboxymethylene-2-methallyl-2-,4b-dimethyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol and 15 mg. of p-toluene sulfonic acid in 3ml. of acetone for a period of about 20 minutes, there is obtainedl-carboxymethylene-Z-methallyl 2,4b dimethyl1,2,3,4,4a,4b,5,6,7,9,l0,10a-dodecahydrophenanthrene-4-ol-7-one.

Example 4 A suspension of 5 g. of 1-carboxymethylene-Z-methallyl 2,4bdimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,lO,lOa-dodecahydrophenanthrene-4-one in 20 ml. of tetrahydrofuran and200 rrrl. of liquid ammonia was stirred at a temperature of 40 C. whilepea-sized portions' of lithium were added at intervals and at a ratesuflicient to maintain an excess of the alkali metal. The liquid ammoniareaction mixture was stirred at a temperature of about 40 C. for a totaltime of about two hours during which the addition of the lithium wascontinued; a total of about 500 mg. of lithium was used.

The excess ammonia was evaporated from the reaction mixture at roomtemperature, about 200 ml. of benzene was added, and ethyl acetate wasthen added cautiously to detroy the excess lithium. One hundred andfifty milliliters of water was added to the mixture and the benzenelayer was discarded. The alkaline aqueous layer was acidified withexcess sodium dihydrogen phosphate and the acidified aqueous mixtureextracted with chloroform. The chloroform extract was washed with water,dried over anhydrous sodium sulfate, filtered, and

the chloroform evaporated from the filtered solution under reducedpressure. The residual oil was covered with 50 ml. of ether and themixture heated under reflux for about fifteen minutes. The crystallineprecipitate which formed was recovered by cooling the ethereal mixtureand filtering. This crystalline material was fractionally crystallizedfrom acetonitrilc to give l-carboxymethyl-Z- methallyl 2,4bdimethyl-7-ethylenedioxy-l,2,3,4,4a,4b, 5,6,7,8,l0,10adodecahydrophenanthrene-4-one, which crystallized first, andl-carboxymethyl-2-methallyl-2,4bdimethyl 7ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol(the more soluble com- In accordancewith. the foregoing experimentalprocedure and utilizing as starting material the stereoisomer 2methallyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,

5,6,7,8, 10, lOa-dodecahydrophenanthrene-4-one having an M.P. of 201-203C., and two stereoisomers of l-carboxymethylZ-methallyl-Z,4b-dimethyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4-01, one of which has an M.P. of 226-228 C..and. the other an M.P. of 234-235 C. T

When the stereoisomer of l-carboxymethyl-3-methallyl 2,4bdimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,10,10adodecahydrophenenanthreneA-one having an M.P. of 203-205 C. was used asstarting material there were obtained two stereoisomers of1-carboxymethyl-2- methallyl 2,4b dimethyl 7-ethylenedioxyr 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol one of which has an M.P.of 255257 C. and the other an MP. of 216--220 C.

When l-carboxymethylene-2-methallyl-2,4b dimethyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol was utilizedas starting materialin the foregoing procedure, the product obtained-was1- carboxymethyl 2 methallyl 2,4b dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol.

A solution containing about 50 mg. of l-carboxymethyl- 2 methallyl2,4b-dimethyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene 4 4 01 and about 15 mg. ofp-toluene sulfonic acid in about 3 ml. of acetone was heated underreflux for a period of about twenty minutes. The acetone reactionmixturewas diluted with water and the resulting aqueous mixtureextracted with chloroform. The chloroform extract .was dried andevaporated to dryness to give l-carboxy-methyl- 2 methallyl2,4b-dimethyl-1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4-ol-7-one.When the stereoisomer of 1-carboxymethyl-2-methally1-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-4-olhaving an'M.P. of 255-257 C. was hydrolyzed in accordance with theforegoing procedure there was obtained the stereoisomer ofl-carboxymethyl- 2 methallyl2,4b-dimethyl-1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4-ol-7-onehaving an ;M.P. of 215-217" C.; when the stereoisomer of 1-carboxymethl2 methallyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol having an M.P. of 216-220"C. was similarly hydrolyzed there was obtained the stereoisomer ofl-carboxymethyl-Z-methallyl2,4b-dimethyl-1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-4-ol-7-onehaving an M.P. of 192 C.

When 1-carboxymethyl-2-methal1yl-2,4b-dimethyl -.7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-4-one is similarlyhydrolyzed using an acetone solution of p-toluene sulfonic acid, thereis obtained 1 carboxymethyl 2-methallyl-2,4b-dimethyl 1,2,3,4,4a,

4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4,7-dione. I

Example 5 One and two-tenths gram of sodium metal was added to 20 ml. ofrefluxing ethyl alcohol, followed immediately v by one-half gram ofl-carboxymethylene-2 methallyl-2, 4bdimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,'l0,10a-

dodecahydrophenanthrene-4-one. The resulting ture was stirred vigorouslyfor a period of about, fifteen minutes. The reaction mixture wasevaporated to. one- I half volume in vacuo, and the concentratedsolution V diluted with water. The aqueous solution was extracted Onepart of 1-carboxymethylene-2-methallyl-2,4b-dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one, M.P. 203-205C.) was reacted with about 2.4 parts of sodium metalutilizing the sameprocedure as that described in ,Example 5 hereinabove except thatn-butanol was used for the reduction medium in place of ethyl alcohol.The reaction mixture was worked up as in Example 5 to give substantiallypure 1-carboxymethyl-Z-methallyl-2,4b-dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5 ,6,7 ,8,10,10a-dodecahydrophenanthrene-4-ol (M.P.255-257 C.).

Example 7 A mixture of one part of l-carboxymethylene-Z-methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,ladodecahydrophenanthrene 4-one (M.P. 203205 C.), about 4 parts ofpotassium metal, and about 40 ml. of n-butanol was stirred at the refluxtemperature of the solvent for a period of about fifteen minutes. Thereaction mixture was worked up as in Example hereinabove to givesubstantially pure l-carboxymethyl 2 methallyl 2,4bdimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-o1 (M.P. 255-257 C.).

Example 8 A solution of 2.75 g. of 1-carboxymethyl-2-methallyl- 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol' was treated with an excess ofdiazomethane in ether. After standing overnight at room temperature, thesolvents were removed by evaporation. The residual oil was crystallizedfrom ether, and the crystalline material thus obtained recrystallizedfrom a mixture of ethyl acetate, ether, and petroleum ether to givesubstantially pure l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 carboxymethyl2-methallyl-2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-4-ol having an M.P.of 226-228 0., there was obtained the stereoisomer ofcarbomethoxymethyl-2- methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a, 4b,5,6,7,8,10,10a dodecahydrophenanthrenei-ol having an M.P.of 138139 C.

When the steroisomer of 1-carboxymethyl-2-methallyl- 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 10,lOa-dodecahydrophenanthrene4-olhaving an M.P. of 255-257 C. was used as starting material there wasobtained the stereoisomer of l-carbomethoxymethyl-Z- methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 01 having an M.P. of 157-158 C.

When the stereoisomer of 1-carboxymethyl-Z-methallyl- 2,4b dimethyl 7ethylenedioxy 1 ,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol having an M.P. of 2l6220 C. was usedas starting material there was obtained the stereoisomer of1-carbomethoxymethyl-2-methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,

5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol having art M.P. of 83-85 C.

A solution containing about 50 mg. of l-carbomethoxymethyl 2 methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol and about 15 mg. of p-toluene sulfonic acidin about 3 ml. of acetone was heated under reflux for a period of abouttwenty minutes. The acetone reaction mixture was diluted with water andthe resulting aqueous mixture extracted with chloroform. The chloroformextract was dried and evaporated to dryness to give 1-carbomethoxymethyl 2 methallyl -.2,4b.- dimethyl-1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene- 4-ol-7-one. Whenthe stereoisomer of l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophen'!anthrene-4-ol having an M.P. of 137 -138" C. was used as startingmaterial, there was obtained the stereoisomer of1-carbomethoxymethyl-Z-methallyl-2,4b-dimethyl-1,2,3;4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene -'4'-ol- 7-one having anM.P. of 133-134" C. 1

Example 9 .A suspension of 4.15 g. of l-carboxymethyl-Lmethallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol and 8 g. of anhydrouspotassium carbonate in 50 ml. of dry-acetone containing 8 ml. of methyliodide was stirred, in a looselystoppered flask, at room temperature fora period of about fifteen hours. The reaction solution was filteredthereby removing the precipitated potassium iodide and excess potassiumcarbonate. The acetone was evaporated from the filtered solution invacuo, and the residual oil' 'was dissolved in ether; the etherealsolution was washed twice with 10 ml.-portions of water, dried overanhydrous sodium sulfate, and the solvents evaporated. The residual oilwas crystallized from ether and dried to give substantially pure 1carbomethoxymethyl 2-methallyl-2,4b-dimethyl 7 ethylenedioxy-,1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4 ol.

In accordance with the foregoing experimental procedure and utilizingthe stereoisomer of l-carboxymethyl 2 methallyl 2,4b dimethyl 7ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene-4-01 having an M.P.. of 216-220 C. as starting material, there wasobtained the stereoisomer of l-carbomethoxymethyl 2 methallyl 2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol having an M.P. of 83-85 C. 1

Example 10 A solution of 350 mg. of l-carbomethoxymethyl-Z- methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol in 3.5 ml. of pyridinewas added to the complex formedpby adding 350 mg. of chromium trioxideto 3.5ml. of pyridine. The resulting mixture was shaken, and allowed tostand at room temperature in a closed vessel for a period of aboutfifteen hours. The reaction mixture was diluted with about 30 ml. ofwater, and the aqueous solution was extracted with three 50 ml.-portionsof ether. The ethereal extracts were combined, washed twice with water,dried over anhydrous sodium sulfate, and the solvent evaporated. Theresidual oil was crystallized twice from ether to give substantiallypure l-carbomethoxymethyl-Z- methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4, 4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 carbomethoxymethyl 2 methallyl2,4b di methyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a;dodecahydrophenanthrene-4-ol having an M.P. of,il38 139 C., there wasobtained the stereoisomer of l-carbomethoxymethyl 2 methallyl 2,4bdimethyl -v 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahyassassin drophenanthrene-40m having an MP. "of 125-42 17 C.;when the stereoisomer of l-carbomethoxymethyl 2-metha]ly1--2,4b dimethy17 'ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10;10a--dodecahydrophenanthrene-4-ol having an M.P. of 157-158 C. was used asstarting material there was-obtained the stereoisomer ofl-carbomethoxymethyl- 2 methallyl 2,4b-- dimethyl 7ethylenedioxy--.1,2,3, 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4one having an M.P. of 140-141" C.; when the stereoisomer "ofl-carbomethoxymethyl-2-methallyl-2,4b-dimethyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a -.dodeca hydrophenanthrene-4-ol having anM.P. of 8385 C. was used as starting material there was obtained thestereoisomer of 1-carbomethoxymethyl-2-methallyl-2,4bdimethyl 7ethylenedioxy1,2,3-,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one.having anM.P. of .142- 146 C.

.When the stereoisomer of v1-carboxymethyl-2-.methallyl -2,4b dimethyl 7ethylenedioxy .1,2,3,4,4a,4b, 5,6,7,8,10,10a dodecahydrophenanthrene 4olhaving an M.P. of 234-235 C. was reacted with diazomethane in ether inaccordance with the procedure described in Example 8 hereinabove, andthe resulting stereoisomer of '1 -carbomethoxymethyl 2 methallyl 2,4bdimethyl 7 --ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene-4-ol reacted with chromium trioxidepyridine complex'in accordance with the procedure described in the present example therewas obtained the stereoisomer ofl-carbomethoxymethyl-Z-methallyl-2,4bdimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene 4 one having anM.P. of 155 C.

Upon heating together, under reflux, l-carbomethoxymethyl 2 methallyl2,4b dimethyl 7 ethylene dioxy 1,2,3,4,4a,4b,5,6,7,8,'10,1'0a'dodecahydro phenanthrenet-one and an acetone solution of .ptoluenesulfonic acid, whereby the ethylenedioxy substituent is hydrolyzedwithout appreciably affecting the carbomethoxy ester grouping, there isobtained l-carbomethoxymethyl l,2,3,4,4a,4b,5,6,7,8,9,10,10a dodecahydrophenanthrene-4,7-dione.

Example 11 To a solution of 378 mg. of l-carbomethoxymethyl-2-methallyl-2,4b-dimethyl-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,la-dodecahydrophenanthrene-4-one in 3 ml. of dry ether and 0.5ml. of dry benzene was added 254 mg. of osmium tetroxide. The resultingsolution began to deposit in a few minutes a brown-black precipitatewhich can be recovered by filtration and dried to give the osmate esterof l-carbomethoxymethyl .2 (beta,gamma-dihydroxyisobutyl) 2,4b dimethyl7 .ethylenedioxy 1,'2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene4-one. Instead of isolating the osmate ester, the reaction mixture wasallowed to stand at room temperature for a period of one hour, and 18ml. of ethanol was then added to the reaction mixture. A solution of 0.8g. of anhydrous sodium sulfite in 9 ml. of water was added to thealcoholic reaction mixture, the resulting mixture was vigorouslyagitated for a period of about three minutes, and the precipitatedosmium oxide removed by filtration. The filtered reaction solution wascautiously acidified with dilute acetic acid to a pH of about 6, and themildly acid aqueous solution was evaporated under reduced pressure to anoil. Water was added to the oil, and the aqueous mixture was extractedwith ether. The ether extract was washed with water, dried overanhydrous sodium sulfate, and the ether evaporated. The residualcrystalline material was crystallized from ethyl acetate to give 1carbomethoxymethyl 2 (beta,gamma 'dihy 'droxyisobutyl) 2,4b di-methy1--7 ethylenedioxy 1,2, '3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene 4one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of 1 'earbomethoxymethyl- 2 methallyl2,4b di methyl --'7 ethylenedioxy 1,2,3;4,4a,4b,5,6;7,8,10,10adodecahydrophenanthrene-4-one having ian'M.'P. of 1-25- 127" C.,'therewas obtained the stereoisomer of l-carbomethoxymethyl 2 (beta,gammadihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one having an M.P. of 172-174 C.;when the stereoisomer of l-carbomethoxymethyl 2 .methallyl 2,4b dimethyl7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M.P. of -141 C. was used as startingmaterial, there was obtained the stereoisomer of l carbomethoxymethyl 2(beta,- gamma dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,l0,l0a dodecahy drophenanthrene-Lone having anM.P. of 142-155 C.; when the stereoisomer of l-carbomethoxymethyl 2methallyl -"2,4b dimethyl 7 ethylenedioxy 1,2,3,'4,4a,4b,5,6,7,8,1'0,1'0a dodecahydrophenanthrene 4 one having an M.P. of142-146 C. was used as'starting material, there was obtained thestereoisomer of l-car'bomethoxymethyl 2 (beta,gamma dihydroxyisobutyl)2,4b dimethyl 7- ethylenedioxy- 1,2,3,4,4a,4b,5,6',7, 8,10,.10adodecahydrophenanthrene -4 one having an M.P. of 143147 C.

Upon heating together, under reflux, l-carbomethoxymethyl 2 (beta,gammadihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,l0, 10a'- dodecahydrophenanthrene 4 one and anacetone solution of p-toluene sulfonic acid, whereby the ethylenedioxysubstituent is hydrolyzed without appreciably affecting the carbomethoxyester grouping, there is obtained 1 carbomethoxymethyl 2 (beta,gammadihydroxy isobutyl) 2,4b dimethyl l,2,3,4,4a,4b,5,6,7,9,10,1021-dodecahydrophenanthrene 4,7 dione.

Example 12 To a solution of 400 mg. of 1-carbomethoxymethyl-2-(beta,gamma dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5, 6,7,8,10,10a dodecahy drophenanthrene 4 one in 4 ml. ofethanol was added 1 ml. of pyridine and a solution of 350 mg. ofperiodic acid in 2 ml. of water. The resulting mixture was allowed tostand vfor a period of about six minutes at the end of which time theexothermic reaction which occurred was substantially complete. Thereaction mixture was diluted with 20 ml. of water, and the aqueousmixture extracted with ether. The ether extract was Washed with 5 ml. ofwater, dried over sodium sulfate, filtered and the ether evaporated. Theresidual oil was crystallized from petroleum ether to give substantiallypure l-carbomethoxymethyl 2 acetonyl 2,4b dimethyl 7 ethylenedi oxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenan threne-4-one.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of l-carbomethoxymethyl 2(beta,gamma-dihydroxyisobw tyl)2,4b-dimethyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene-4-one having an M.P. of 172-174 C. therewas obtained the stereoisomer ofl-carbomethoxymethyl-2-acetonyl-2,4b-dimethyl-7-ethylenedioxy-l,2,3,4,4a,4b, 5, 6, 7, 8, 10, 10adodecahydrophenanthrene-4-one which crystallized from ether in a crystalform having an M.P. of 108-109 C. and which crystallized from ethylacetate-petroleum ether in a crystal form having an M.P. of 8595 C.;when the stereoisomer oflcarbomethoxymethyl-2-(beta,gamma-dihydroxyisobutyl)-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-onehaving an M.P. of 142- C. was used as starting material there wasobtained the stereoisomer of 1-carbomethoxymethyl-2-acetonyl-2,-4b-dimethyl-7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene-4-one having an M.P.of 132- 134 C.; when the stereoisomer of l-carboxymethoxymethyl-2.-(beta,gamma-dihydroxyisobutyl) -2,4b-dimethyl-.7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 143-147 C. was

used asstarting material, there was obtained the stereoisomer of1-carbomethoxymethyl-2-acetonyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4ronehaving an M.P. of 144 C.

1 Upon heating together under reflux,l-carbomethoxymethyl-Z-acetonyl-2,4b-dimethyl-7-ethy1enedioxy1,2,3,4,-4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one and an acetonesolution of p-toluene sulfonic acid, there is obtained1-carbomethoxymethyl-2-acetonyl-2,4b dimethyl- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4, 7-dione.

Example 13 One gram of 1-carbomethoxymethyl-2-methallyl-2,4b-

dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one was dissolvedin 100 ml. of methanol. The resulting solution was cooled to atemperature of about -80" C. and a stream of ozonized oxygen containingone equivalent of ozone was;passed, over a two-minute period, throughthe cold solution. The reaction mixture was warmed to a temperature ofabout C., and 10 m1. of water was added to the mixture followed by fivegrams of zinc and ml. of acetic acid. The resulting mixture was stirredfor a period of about thirty minutes. Water and solid sodium carbonatewere then added, the mixture was filtered, and the solvents wereevaporated from the filtered solution in vacuo while maintaining thetemperature of the solution below about 20 C. The residualmaterial wasextracted with ether and ether solution chromatographed on acid-washedalumina. Upon evaporation of the ether-petroleum ether eluate there wasobtained1-carbomethoxymethyl-2-acetonyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,-10,10a-dodecahydrophenanthrene-4-one. In accordance with theforegoingexperimental-procedure and utilizing as starting material thestereoisomer of1-carbomethoxymethyl-2-methallyl-2,4b-dimethyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenenthrene-4-onehaving an M.P. of 125-127" C., there was obtained the stereoisomer of1-carbomethoxymethyl-2-acetonyl-2,4b-dimethyl-7-ethylenedioxy+1,2,3,4,4a,4b,5-6,-7,8,10,10a-dodecahydrophenanthrene-4-one having an M.P. of 108-109 C.when crystallized from ether.

Example 14 A solution of 506 mg. ofl-carbomethoxymethyl-Z-acetonyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,-10,1(la-dodecahydrophenanthrenel-one in benzene was distilled at roomtemperature until the volume of the solution was about ml. Thisprocedure assured a dry solution. This dry solution was'added to solidsodium methoxide. (The solid sodium methoxide was prepared by removingthe excess methanol from 2.4 ml. of a 1 molar methanol solution ofsodium methoxide by baking at 150 C. for thirty minutes in vacuo.) Themixture of the benzene solution of the hydrophenanthrene compound andthe solid sodium methoxide was allowed to stand at room temperature fora period of about twenty minutes at the end of which time a flocculentsolid precipitated from the benzene solution. The resulting mixture wasstirred at room temperature for a period ofabout fifteen hours. Amixture of cold water (0 C.) and ether was added to the reaction productand the resulting mixture was vigorously agitated. The aqueous phase wasquickly separated and immediately acidified with an excess of an aqueoussolution of sodium dihydrogen phosphate. The acidified aqueous solutionwas extracted with chloroform, and the organic extract was dried overanhydrous sodium sulfate, filtered, and the chloroform evaporated. Theresidual crystalline material was recrystallized from ethylacetate-ether, and from ethanol/to give A -3-ethylenedioxy-l1,16,20-triketo-pregnene. V

In accordance with the foregoing experimental proce- 22 dureandutilizing as starting material the stereoisomer of1-carbomethoxymethyl-Z-acetonyl2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-onehavingan M.P. of 132-134 C. there was obtained the stereoisomer of A-3-ethylenedioxy-11,16,20- triketo-pregnene having an M.P. of 154-156"C.; when the stereoisomer of 1-carbomethoxymethyl-2-acetonyl-Z;4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene-4-one having whencrystallized from ether, an M.P. of 108-109" C., there was obtained thestereoisomer of A -3-ethylenedioxy-11,16,20-triketopregnene having anM.P. of 226-229" C. when the stereoisomer of1-carbomethoxymethyl-Z-acetonyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one, having anM.P. of 144 C. was used as starting material, there was obtained thestereoisomer of A -3-ethylenedioxy-11,16,20-triketo-pregnene having anM.P. of 213-215" C.

Upon heating together, under reflux, A-3-ethylenedioxy-l1,16,20-triketo-pregnene and an acetone solution ofp-toluene sulfonic acid (substantially in accordance with To a solutionof 295 mg. of A -3-ethylenedioxy-1L16. ZO-triketo-pregnene in 3.7 ml. ofpyridine was added 370 mg. of p-toluenesulfonyl chloride. The resultingmixture was allowed to stand at room temperature for about twenty-twohours. At the end of this period 2.3 ml. of saturated aqueous sodiumbicarbonate solution were added to the cooled reaction mixture, therebyneutralizing the pyridine hydrochloride formed by the reaction as wellas the excess p-toluenesulfonyl chloride. The aqueous pyridine mixturewas agitated at room temperature for a period of about fifteen minutesduring which time a crystalline product precipitated. Benzene was addedto the reaction mixture, the mixture was poured onto ice, and diluteaqueous hydrochloric acid was added until the mixture was just acid. Theorganic layer was rapidly separated, washed with water, and with aqueoussodium bicarbonate solution. The washed organic layer was dried oversodium sulfate, and evaporated to dryness in vacuo. The residualmaterial was recrystallized from benzene-petroleum etherether and thenchromatographed on acid-washed alumina. The material obtained from the1:1 petroleum ether-ether eluate was recrystallized from benzene-etherto give substantially pure A -3- ethylenedioxy 16 p toluenesulfonoxy11,20 diketopregnadiene.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of A-3-ethylenedioxy-l1,16,20-triketo-pregnene having an M.P. of 154-156"C., there was obtained the stereoisomer of A-3-ethylenedioxy-16-p-toluenesulfonoxy-l1, ZO-diketo-pregnadiene havingan M.P. of 199-201" C.; when the stereoisomer of A-3-ethylenedioxy-11,16,20-triketo-pregnene having an M.P. of 226-229" C.was used as starting material, there was obtained the stereoisomer of A-3-ethylenedioxy-16-p-toluenesulfonoxy-11,20-diketo-pregnadiene havingan M.P. of 189-190" C.; when the stereoisomer of A-3-ethylenedioxy-11,16,20-triketopregnene having an M.P. of 213-215" C.was used as starting material, there was obtained the stereoisomer of A-3-ethylenedioxy-16-p-toluensulfonoxy-11,20 diketopregnadiene having anM.P. of 198-200" C.

Upon heating together, under reflux, A-3-ethylenedioxy-16-p-toluenesulfonoxy-11,20-diketo-pregnadiene and anacetone solution of p-toluene sulfonic acid, thereifl aesaaea obtained a-.1Gptoluenesulfonoxy-B,1.1;20-triketo pregnadiene.

Example 716 'To a solution of 52 mg. of A-3-ethylenedioxy-16-ptoluenesulfonoxy-l1,20-diketo-pregnadiene in 10 m1.of benzene was added 2 g. of palladium catalyst (5% Pd on BaCO and themixture was shaken at room temperature in contact with hydrogen undera'pressure of about forty pounds per square inch. After about two hours,'an additional 0.8 g. of catalyst was added and, after four more hours,another 0.8 g. of catalyst was added to the hydrogenation mixture. Theresulting mixture was shaken for an additional fifteenhour period atroom temperature in contact with hydrogen at a pressure of forty poundsper square inch. The reaction mixture was filtered thereby removing thecatalyst and the benzene was evaporated from the 'filtered solution invacuo. The residual material was treated with ether and the crystallineproduct thusobtained was recrystallized from ether-petroleum ether-etherto give substantially pure A 3-ethylenedioxy- 1 1,'20-diketo-pregnene.

In accordance with the foregoing experimental procedure and utilizing asstarting material the stereoisomer of A-3-ethylenedioxy-16-p-toluenesulfonoxy-l1,20-diketo-pr'egnadiene havingan M.P. of 199-201 C. (which was prepared using the stereoisomer of A-3-ethylenedioxy-l1,'16,20-triketo-pregnene of M.P. 154-156 C.) therewas obtained the stereoisomer of A -3-ethylenedioxy-l1,20-diketo-pregnene having an M.P. of 181-182.5 when thestereoisomer of A -3-ethylenedioxy-l6-ptoluenesulfonoxy 11,20 diketopregnadiene having an M.P. of 189-190 C. was used as starting material,there was obtained the stereoisomer of A -3-ethylenedioxy-1l,'20-diketo-pregnene having an M.P. of 142-145 C.; when the.stere'oisomer of A -3-ethyIenedioXy-I6-p-toluenesul-'fonoxy-l1,20-diketo-pregnadiene'having an M.P. of 198- 200 C.(prepared, in turn, from the stereoisomer of A 3 .ethylenedioxy 11,16,20triketo pregnene of M.P. 213-215 C.) there was obtained the stereoisomerof A 3-ethylenedioxy-11,20-pregnene, having an M.P. of 171-.172 C.

Each of the three stereoisomers of A -3-ethylenedioxy-11,20-diketo-pregnene, when prepared as described in the presentexample, are obtained in the form of racemates; i.e. dl-A-3-ethylenedioxy-11,20-diketo-pregnene of 'M.P. 181-1825 C.; 'dl-A-3-ethylenedioxy-11,20-diketo-pregnene of M.P. 142-45 C.; and dl-A-3-ethy-lenedioxy- 11,10-diketo-pregnene of M.P. 171-172 C.

Example 17 To a solution of 20 mg. of A -3-ethylenedioxy-11,20-diketo-pregnene .in 1 ml. of tetrahydrofuran was added 0.5 ml. of 3 Naqueous perchloric acid solution. The

reaction mixture was allowed to stand at room. temperature for a periodof approximately three and one-half hours. The solvents were evaporatedfrom the reaction mixture in vacuo, and the residual material wasextracted with chloroform. The chloroform extract was dried over sodiumsulfate, and the solvent evaporated from the dry chloroform extract invacuo. The residual material was recrystallized from ether to give A-3,l1,20-triketo-pregnene.

In accordance with the foregoing experimental procedure and utilizingthe racemate of A -3-ethylenedioxy- 11,20-diketo-pregnene having an M.P.of l81-182.5 C. as starting material, there was obtained the racemate of-A -3,11,20-diketo-pregnene having an M.P. of 175.5- 1765' C.; when theracemate of A -3-ethylenedioxyll,20-diketo-pregnene having an M.P. of142-145 C. was'u'sed as starting material, there was obtained theracemate of A -3,11,20-triketo pregnene having an 'M.P. of 153-158" 0;when the racemate of A 3-ethylenedi- 'oxy-l1,20-diketo=pregnene havingan M.P. of 171-172 C. was used as starting material, there was obtainedthe 24 raeemate .of JABJLZO-ttik to-pregnene having an 615153 C.andi1'68 C. (dimorphic).

The racemate MAE-3,1 1,20-triketoqaregnene having an M.P. of 175.5.176.5C. possesses the stereoisomericconfiguration characteristic of thenaturally occurring'steroid hormones such as progesterone; we referto'this'racemate (M.P. 175.5-176.5 C.) as dl-ll-keto-progesterone.

Example 18 To a solution-of 222 mg. of l-ethoxyethinyl-Z-methallyl- 2 4b.dimethyl 7 ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10adodecahydrophenanthrene 1,4 diol (M.P. 108-111" C.) in 2 ml. oftetrahydrofuran was added 0.008 ml. of concentrated sulfuric acid. Afterthree minutes at room temperature, an excess of sodium bicarbonatesolution was added to the reaction mixture and the tetrahydrofuran wasevaporated. The organic material which separated was extracted intoether; the ether extract was washed once with water, dried overmagnesium sulfate andthe ether was evaporated. The residual oilymaterial was dissolved in benzene and chromatographed on acid-washedalumina. The ad sorbate was eluted with mixtures of ether and petroleumether; upon evaporation of the 2:8 ether-petroleum ether eluate therewas obtained 1-carbethoxymethylene-2- methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01which melted at -420 C. after purification by recrystallization fromether-petroleum ether.

Example 19 A suspension of 60 mg. of l-carbethoxymethylene 2- methallyl2,4b dimethyl 7 ethylenedioxy l,2,3,4, 4a,4b,'5,6,7,8,'10,l0a--dodecahydrophenanthrene 4 ol (M.P. 105120 C.) 'in '5 ml. of methanol and5 ml. 'of water containing 0.5 g. of potassium carbonate and l'ml. of lN potassium hydroxide'was heated under reflux for three hours. Themethanol was evaporated under reduced pressure and the iaqueous'residuewas diluted with water and extracted with ether to remove any neutralmaterial. The aqueous solution was acidified with excess sodiumdihydrogen phosphate and the acidified mixture was extracted withchloroform. After drying over magnesium sulfate, the chloroform extractwas filtered and evaporated to dryness under reduced pressure. Theresidual material was crystallized from benzene-petroleum ether to givesubstantially pure 1 carboxymethylene 2- methallyl 2,4b dimethyl 7ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 olmeltingat 174-180 C.

Treatment of the l carboxymethylene 2 methallyl- 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6, 7,8,10,10a-dodecahydrophenanthrene-4-olwith a slight excess of diazomethane in ether solution gavel-carbomethoxymethylene 2 methallyl 2,4b dimethyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahy drophenanthrene-4-ol, M.P.134-135 C.

Oxidation of the 1-carbomethoxymethylene-2-metl1- allyl 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,l0,10a dodecahydrophenanthrene 4 ol(M.P. 134-135 C.) with chromic anhydride and pyridine gave astereoisomer of 1-carbomethoxymethylene-Z-methallyl- 2,4b dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6, 7,8,10,10adodecahydrophenanthrene 4 oneM.P. 153 C.

Example 20 A solution of 229 mg. of 1-carboxyrnethylene-2-rncthallyl2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol in 5 ml. of ether was addedto a solution of 40 mg. of lithium in 10 ml. of liquid ammonia at -78 C.The liquid ammonia reaction mixture was allowed to warm to 40 C. withstirring. After twenty minutes the blue lithium color was discharged.Anadditional 40 mg. of lithium was added and the mixture was stirred at-40-C. for an additional hour. The excess ammonia was evaporated fromthe reaction mixture at room temperature and ml. of ether was added.Ethyl acetate was then added cautiously to destroy the excess lithium.Water was added to the mixture and the ether layer was discarded. Thealkaline aqueous layer was acidified with excess sodium dihydrogenphosphate and the acidic product was extracted with chloroform. Thechloroform extract was washed with water, dried over magnesium sulfate,filtered, and the chloroform evaporated under reduced pressure.Crystallization of the residue from benzene gave subtantially pure 1carboxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,1021- dodecahydrophenanthrene-4-ol melting at195-l97 C.

Oxidation of the 1-carboxymethyl-2-methallyl-2,4b-dimethyl 7ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-01with chromic anhydride and pyridine gave1-carboxymethyl-Z-methallyl-Z,4b-dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one.

Treatment of the 1-carboxymethyl-Z-methal1yl-2,4b-dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-olwith a slight excess of diazomethane in ether solution gavel-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dode'cahydrophenanthrene-4-ol; M.P.142-144" C.

Example 21 One gram of 1-carboxymethyl-Z-methallyl-2,4b-dimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-onewas dissolved in 30 ml. of water containing 1.1 m1. of 4 N aqueoussodium hydroxide and ml. of ethanol. One gram of sodium borohydride wasadded, and the solution was allowed to stand at room temperatureovernight. One more gram of sodium borohydride was added, and thesolution was boiled 1% hours. It was poured into ice water, andacidified with excess sodium dihydrogen phosphate. The acid mixture wasextracted twice with chloroform, the combined extracts were evaporated,and the amorphous residue was crystallized from ether. Recrystallizationfrom ethyl acetate and from tetrahydrofuran-petroleum ether aiforded 1carboxymethyl 2 methallyl 2,4b-dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-01, M.P. 167-169 CExample 22 To a solution of 20.7 g. of 1-ethoxyethinyl-2-allyl-2, 4bdimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene-1-ol-4 one (M.P. 83.5- 85.0 C.) in 165 ml.of absolute tetrahydrofuran was added 12.0 ml. of 10% aqueous sulfuricacid. The temperature of the solution was maintained at a temperature of28 30 C. for a period of three and one-half hours. After the first 45minutes had elapsed, there was added 0.17 ml. of pyridine, and thereaction mixture was stirred for the remaining time. The reaction wasquenched by the addition of excess aqueous sodium bicarbonate. The

. organic solvent was distilled off in vacuo and theremainethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-l-ol-4-one melting at 159160 0., there wasobtained the stereoisomer of. l-carboethoxymethyl- 26 2-al1yl2,4b-dimethyl 7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-l-ol 4 one, M.P. 101 C.

Example 23 A solution of 175 mg. of l-carboethoxymethylene-Z-al1y1-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in 2.9 ml. of methanol was treatedwith a solution of 0.37 g. of potassium carbonate in 2.7 ml. of water.The resulting mixture was heated to boiling under reflux for a period oftwo and one-half hours. The methanol was removed under reduced pressureand the aqueous solution acidified with excess sodium dihydrogenphosphate. An ether extraction was made of the solution, and the extractwashed with water, dried over magnesium sulfate, and concentrated invacuo. The resulting oil crystallized from petroleum ether and wasrecrystallized from benzene-petroleum ether to give purel-carboxymethylene-Z- allyl-2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene-4-one, having amelting point of 163-164 C.

Example 24 A suspension of 14.2 g. of l-carboxymethylene-2-ally1-2,4b-dimethy1-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one (M.P. 163-164 C.) in 225 ml. of waterwas dissolved by adding one molar equivalent of aqueous sodiumhydroxide. To this solution was added 21 g. of sodium borohydride, andthe mixture was allowed to stand overnight. The reaction mixture wasthen heated at C. for one hour, cooled, and acidified with sodiumdihydrogen phosphate. Extraction of the aqueous solution withchloroform, followed by washing the extract with water, drying overmagnesium sulfate, and concentrating to dryness under reduced pressuregave 1-carboxymethylene-2-allyl-2,4b-dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol, an amorphoussolid.

Example 25 l-carboxymethylene-Z-allyl 2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one (15 g. ofamorphous material) was added to one liter of anhydrous ammonia cooledto a temperature of 60 C. followed by the addition of 15 g. of metallicpotassium. There was then introduced 50 ml. of anhydrous isopropanolover a period of five minutes. The mixture was stirred until thereaction was over as evidenced by the disappearance of the blue colorcharacteristic of metallic potassium in liquid ammonia. The ammonia wasallowed to evaporate overnight. The remaining solution was thenconcentrated almost to dryness under reduced pressure. Two hundredmilliliters of water were added followed by addition of a solution of 70g. of sodium dihydrogen phosphate and 50 g. of 85% phosphoric acid in500 ml. of water. The crystalline material thus obtained was filteredand washed thoroughly with water, yielding l-carboxymethyl-Z-allyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol, M.P. 235.5236.0 C.

Example 26 To a solution of 10.90 g. of l-carboxymethyl-Z-allyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, 10adodecahydrophenanthrene 4 ol (M.P. 235.5- 236.0 C.) in one liter ofabsolute tetrahydrofuran was added an excess of diazomethane in ether.After standing overnight at room temperature, the solvents were re movedby evaporation, and the residual material crystallized from ethylacetate-petroleum ether to give substantially pure1-carbomethoxymethyl-2-allyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol, M.P. 113115 C. Recrystallization of thismaterial from aqueous methanol gave a second crystallinemodification,M.P. -132 C.

27 Example '27 A mixture of 15.80 g. of1-carboxymethyl-2-allyl-2;4bdimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol and 40 g. ofanhydrous potassium carbonate in 450 ml, of acetone and 40 ml. of methyliodide was stirred at room temperature for 42 hours. The solvent wasthen distilled off under reduced pressure and the residue treated with100 ml. of water. The mixture was then extracted with chloroform, theextract washed with water, dried over magnesium sulfate. andconcentrated to dryness in vacuo. The residual oil was taken up in asmall volume of methanol and crystallized by addition of water, to givesubstantially pure 1- carbornethoxymethyl-2-allyl-2,4b-dimethyl-7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol.

Example 28 --A solution of 9.35 g. of l-carbomethoxymethyl-Z- allyl 2,4bdimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,1(la-dodecahydrophenanthrene-4-ol in 1.00 ml. of pyridinewas added to the complex formed by adding 10 g. of chromium trioxide to100 ml. of pyridine. After standing at room temperature overnight, theresulting mixture was diluted with an equal volume of water. Thesolution was then extracted with ether, and the extract washed withwater, dried over magnesium sulfate, and concentrated to about 100 ml.One hundred milliliters of methanol were then added followed by additionof 500 ml. of water. The material which crystallized was filtered anddried to give l-carbomethoxymethyl 2 allyl- 2,4b dimethyl 7ethylenedioxy- 1,2,3,4,4a,4b,5,6;7,8,10,10a dodecahydrophenanthrene-4-one crystallized; M.P. 10%-109 C.

Example 29 To a solution of 400 mg. of l-carbomethoxymethyl- 2 allyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in 4 ml. of anhydrousether was added 280 mg. of osmium tetroxide. The resulting mixture wasstirred at room temperature for 45 minutes. To the mixture was added 20ml. of ethanol and a solution of 1.7 g. of sodium sulfite in 11 ml. ofwater. The solution was shaken for 20 minutes and then filtered. Thefiltrate was concentrated to about .10 ml. and extracted withchloroform. The extract was washed with water, dried over magnesiumsulfate, and concentrated to dryness in vacuo. Crystallization of theresidue from benzene-petroleum ether gave l-carbomethoxymethyl-2-(beta,gamma-dihydroxypropyl) 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b.5,6,7,8,10,1021 dodecahydrophenanthrene 4- one, M.P. 163-164"C. Acidification of the aqueous layer from the chloroform extractionwith excess sodium dihydrogen phosphate and extraction with chloroformfollowed by washing the extract with water, drying over magnesiumsulfate, and concentrating to dryness in vacuo, provided 1carbomethoxymethyl 2 (beta, gamma-dihydroxypropyl) 2,4b dimethyl 7ethylenedioxy 1,2, 3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4-onc, which after recrystallization from pyridine-petroleum etherdecomposed at 228 C.

Example 30 Two hundred milligrams of 1-carboethoxymethy1-2- methallyl2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 1 ol- 4-one in ml. of acetone were treated with5 drops of hydrochloric acid and heated under reflux twenty minutes. Theproduct was crystallized from ether to give 1 carboethoxymethyl 2methallyl 2,4b dimethyl 1,2,'3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene.l-ol-'4,7-dione,.M.P. 122-124 C.

2s Example 31 Three hundred milligrams of 1-carboethoxymethyl-2-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,1 0,10adodecahydrophenanthrene 1 ol- 4-one were heated in 10 ml. of 2 Npotassium carbonate in 50% aqueous methanol under reflux for sevenhours. The methanol was removed in vacuo and the resulting alkalinesolution was washed with ether. The washed alkaline solution was thenacidified with excess sodium dihydrogen phosphate followed by extractionwith chloroform, drying and concentration to give crystallinelcarboxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenauthreneel-ol-4-one aftercrystallization from ethyl acetate; M.P. 213-215 C. This compound washeated for a short while in acetone and a trace of hydrochloric acid.Dilution with water gave .1-carboxymethyl-Z-methallyl- 2,4b dimethyl1,2,3,4,4a,5,6,7,9,l0,10a dodecahydrophenanthrene-1-0l-4,7-dione; M.P.205-210 C. (dee.).

Example 32 The 'stereoisomer of 1-carboethoxymethylene-Z-methallyl 2,4b-din1ethyl 7 ethylenedioxy 1,2,3,4,4a,4b, '5,6,7,8,10,10adodecahydrophenanthrene 4 one (M.P. 9496 C.) was hydrolyzed as inExample 30 to give the stereoisomer ofl-carboethoxymethylene-2-methallyl-2,4bdimethyl1,2,3,4,4a,4b,5,6,'7,9,10,10a dodecahydrophenanthrene-4,7-dione; M.P.Ill-112 C.

Example 33 The stereoisomer of 1-carboxymethylene-Z-methallyl- 2,4bdimethyl 7, ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one (M.P. 203-205 C.) was treatedwith diazomethane in ethyl ether to produce the correspondingstereoisomer of l-carbomethoxymethylene 2 methallyl 2,4b dimethyl 7-ethylenedioxy 1,2,3,4,4a,5,6,7,8,10,10a dodecahydrophenanthrene-4-one;M.P. 152-153.5 C.

Example 34 Treatment of 1-earbomethoxymethYl-Z-methallyl-2,4bdimethyl 7-ethylene'dioxy 1,2,3,4,4a,4b,5,6,7,8,10.10adodecahydrophenanthrene-4-ol(M.P. 157-158 C.) with acetyl chloride in pyridine gavel-carbomethoxymethyl- 2 methallyl 2,4b dimethyl 4 acetoxy 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene; M.P.140-141 C.

Treatment of 1-'carbomethoxymethyl-Z-methallyl-2,4bdimethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10adodecahydrophenanthrene-4-ol(M.P. 83-85 C.) with acetyl chloride in pyridine gavel-carbomethoxymethyl- 2 methallyl 2,4b dimethyl 4 acetoxy 7ethylenedioxy 1 ,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene;M.P. -126 C.

Treatment of 1 carboxymethylene-Z-methally-2,4bdimethyl 7 ethylenedioxy1,2,3,4a,4b,5,6,7,8,10,1021- dodecahydrophenanthrene-4-ol (M.P. 2112l4C.) with acetyl chloride in pyridine gave l-carboxymethylene-Z-methallyl 2,4b dimethyl 4 acetoxy 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene; M.P. 125-126" C.

Example 35 29 dodecahydrophenanthrene-l-ole4-one. Afterrecrystallization from petroleum ether the crystalline product had amelting point of 118'-119C.

Example 36 0.9 cc. of ethanedithiol was added to a cooled mixture ofsulfate and .9 g. of 1-carbomethoxymethyl-Z-methallyl- 2,4b dimethyl 4,7diketo 1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene. Afterstanding at room temperature for 3 days, the reaction mixture wasextracted with ether. Evaporation of the ethereal extract gave acrystalline residue which, upon recrystallization, from ether-petroleumether gave crystalline l-carbomethoxymethyl 2 methallyl 2,4b dimethyl1,2,3,4,4a,4b,5,6, 7,9,10,10a dodecahydrophenanthrene 4,7 dione 7-ethylenemercaptol.

The parent 7-ketone may be regenerated by treating this product with a,dilutesolution of hydrochloric acid in acetone.

Example 37 A solution of 4g. of 2-carbomethoxymethyl-2-methallyl2,4b-dimethyl1,2,3,4,4a,4b,5,6,7,9;10,10a-dodecahydrophenanthrene-4,7-dione in 15 ml.of dioxane was treated with 4 g. of B-mercaptoethanol, followed by theaddition of 5 g. of freshly fused zinc chloride and 5 g. of anhydroussodium sulfate The solution was cooled initially in ice and then allowedto stand at room temperature for 3 days. After dilution with water, thereaction mixture was extracted with chloroform. The chloroform extractwas washed with water until neutral, dried and the solvent evaporated invacuo. The residual material was recrystallized from ether to givesubstantially pure 1,- carbomethoxymethyl-Z-methallyl-2,4b-dimethyl1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4,7-dione-7-ethylenehemithioketal. Thehemithioketal, prepared according to the foregoing procedure, exhibitssubstantially no absorption in the ultra violet.

The parent ketone may be reformed by treatment with acetone-hydrochloricacid.

The 1 ethoxyethinyl 2 methallyl 2,4b dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1-ol-4-one used asstarting material in Example 1 hereinabove can be prepared from7-keto-4bmethyl 1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-1,4-diol (the preparation of which is describedin Patent No. 2,617,828, issued November 11, 1952), in accordance withthe following procedure:

Into a 5 liter flask equipped with a stirrer, a 1 liter dropping funneland a sidearm-with condensor attached in distilling position, wereplaced 38.9 g. (0.155 mole) of 4bmethyl 1,2,3,4,4a,5,6,7,9,10,10adodecahydrophenanthrene-1,4-diol-7-one. 40 cc. (0.645 mole) of glycol,2,500 cc. of ethylene dichloride and 0.4 g. (0.002 mole) of p-toluenesulfonic acid. This mixture was set stirring. Enough heat was applied todistill off 3 liters of the azeotrope of the solvent and water, formedas a by-product, during a 3-hour period. During this time an additional1,500 cc. of ethylene dichloride was added to keep the reactants insolution. After 3 hours the reaction mixture was cooled and thoroughlyshaken ,with 50 cc. of the aqueous 1 Normal potassium bicarbonatesolution. The aqueous carbonate layer was drawn off and twice extractedwith ethylenev dichloride. All three ethylene dichloride extracts werethen combined, dried over anhydrous magnesium sulfate and concentrated.This concentrate was taken up in 1 liter of acetone and concentrateduntil crystals just began to come out. Filtration of the cold acetonegives the crude crystalline product 4bmethyl 7 ethylenedioxy1,2,3,4,4a,4b,5 ,6,7,8,10,10adodecahydrophenanthrene-1,4-diol which canbe further purified by recrystallization from acetone. The pure productmelts at 189 C.

Eighty-six and five tenths grams (0.294 mole) of 4bmethyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-

30 dodecahydrophenanthrene 1,4 diol was dissolved in 2,130 g. (2,250cc.) (21.7 moles) of cyclohexanone, and 2,250 cc. of benzene. To thissolution was added 86.5 g. (0.424 mole) of aluminum isopropoxide, andthe whole was then set to reflux for 12 hours. At the end of this time25 cc. of water was added. The coagulated aluminum hydroxide thus formedwas filtered ofi. The filtrate was concentrated and dried in vacuo,leaving a residue which, on trituration with petroleum ether, gave thecrude crystalline product 4b-methyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4- ol-l-one. It canbe purified by recrystallization from acetone and melts at 219220 C.

To 10.0 g. of 4b-methyl-7-ethylenedioxy-1,2,3,4,4a,4b, 5,6,7,8,10,10adodecahydrophenanthrene 4 ol 1 one dissolved in ml. of benzene and 70ml. of t-butyl alcohol was added, at reflux temperature, 1.5 equivalentsof 1 M potassium t-butoxide in t-butyl alcohol, and 20 ml. of a 1:1solution of methyl iodide in benzene. After 30 minutes of refluxing, thesolution was quenched with water, concentrated in vacuo, and theconcentrate extracted with CHCla. The CHCl extract was dried and thesolvent removed in vacuo. Fractional crystallization of the crystallineresidue from ethyl acetate, yielded the desired product,2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a, 4b,5,6,7,8,10,10adodecahydrophenanthrene 4 ol 1 one, M.P. 189-192 C.

A solution of 3.12 g. of 2,4b-dimethyl-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-lone-4-ol (M.P.189-192 C.) in 30 cc. of pyridine was combined with 3.1 g. of chromiumtrioxide in 30 cc. of pyridine. The reaction flask was stoppered, thecontents mixed thoroughly and allowed to stand at room temperatureovernight. The reaction mixture was poured into water and extracted withthree portions of benzene-ether (1:1) with filtration throughdiatomaceous earth to break the emulsions. After washing with water, thecombined organic solution was dried over anhydrous magnesium sulfate andconcentrated with final drying'of the residue under vacuum.Crystallization from other gave crystalline2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4-dione M.P. C. Chromatography overalumina and elution with petroleum ether-ether (8:2) gave two purifiedisomers, M.P. 135-136 C. and 152-153 C.

A solution of 16.0 g. of crude2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1,4-dione (M.P. 130145 C. and consisting of amixture of isomers M.P. 135-136 C. and 152153 C.') in 190 cc. of benzenewas concentrated to cc. to insure dryness. The solution was then placedunder nitrogen, and treated successively with 16.0 cc. of methallyliodide and 70 cc. of tertiary butyl alcohol containing'2.31 g. ofdissolved potassium. After standing at room tempe'rature for threehours, the mixture was poured into ether, the ethereal solution Washedwith water, concentrated to dryness and purified by chromatography oneither acid washed or alkaline alumina, the product being eluted withpetroleum ether-ether mixtures. Pure2,4bdimethyl-2-methallyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4-dione was obtained, M.P. 108-109"C.

Another isomeric form of this compound having a melting point of 138139C. was also recovered from the chromatographic column.

A solution of ethyl magnesium bromide (0.1526 111.) was prepared in theusual manner from 3.7 g. of magnesium and excess ethyl bromide in 100ml. of dry ether. A solution of 11.74 g. of ethoxyacetylene (0.165 in.)diluted with dry ether to a total volume of 40 ml. was added graduallyto the ethyl Grignard and stirred until the evolution of ethane ceased.120 ml. of dry benzene was added to dissolve the ethoxyacetylenemagnesium bromide.

i Asolution of 27 g. of dry 2,4b-dimethyh2-methallyl 7-ethylenedioxy,1,'2,-3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenedA-dione (stereoisomer of M.P. IDS-109 -C.) in150 ml. of dry benzene was added rapidly to the stirred Grignardsolution. After standingat room temperature for two hours, the reactionmixture was decomposed by pouring into ice-water. Enough saturatedaqueens-ammonium chloride was added to break the emulsion which formed.The benzene-ether layer was separated and washed once with Water. Theaqueous layer was extracted again with 500 ml. of a 1:1 benzene-ethersolu- :tion which, after one Water wash, was combined with the originalextract. After drying over anhydrous sodium sulfate and removal of thelatter by filtration, the solvents "were distilled in vacuo. From asolution'of the residual .oil in ether were obtained crystals of thestereoisomer of :1 :ethoxyethinyl 2,4bdimethyl-Z-methallyl-7-ethylenedioxy 1,2,3,4,4a,4b,'5,6,7,8,10,10adodecahydrophenanithrene-l-ol-4-one having an M.P. of 133-134" C.

By using a stereochemical modification of the above starting material,M.P. 138-l39 C., and treating as above .described, there was obtainedthe stereochemical modiification ofl-ethoxyethinyl-2,4b-dimethyl-2-methallyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro- .phenanthrene-l-ol-4-onehaving an M.P. of 131-132 C.

The1-ethoxyethinyl-2-allyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenc-l-oll-one used as starting material in Example22 hereinabove can be prepared from 2,4b-dimethy1-7-eth- 'ylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene1,4-dione (thepreparation of which is described hereinabove) in accordance with thefollowing procedure:

To a solution containing 4.0 g. of 2,4b-dimethyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4-dione dissolvedin 50 ml. of anhydrous Ibenzene is added m1. of a 1 M solution ofpotassium .t-butoxide in t-butyl alcohol and 3 ml. of allyl iodide. Theresulting solution is allowed to stand at room temperature for a periodof approximately one hour, at the end of which time ice water is addedto the reaction mixture. The aqueous mixture is extracted with ether,and the ethereal extract is evaporated to dryness. The residualcrystalline material is dissolved in benzene-petroleum ether, and thesolutionis chromatographed on acid-washed alumina, and the chromatogramis eluted with etherpetroleum ether. The solvents are evaporated fromthis ether-petroleum ether eluate to give 2-allyl-2,4b-dimethyl- 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene- 1,4-dione.

To an ethereal solution of 2.2 molar equivalents of ethoxyacetylenemagnesium bromide was added 37.5 g. of2-allyl-2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,1()a-dodecahydrophenanthrene-1,4-dione in 950 ml. of benzene. Thereaction mixture was stirred for 2 /2 hours at room temperature. It wasthen poured onto ice water and extracted with ether. The extract waswashed .with water, dried, and concentrated in vacuo. The noncrystallineresidue was chromatographed on 1.6 kg. of alkaline alumina. Withpetroleum ether-ether eluates there was eluted first1-ethoxyethinyl-2-allyl-2,4b-dimethyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-ol-4-one, meltingat 83.5- 85.0 C. after recrystallization from ether-petroleum Cir tionto form 32 ether. Further elution gave a 'stereoisomer of thissubstance, M.P. 159-160 C.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of this invention.

We claim:

1. The process which comprises reacting l-alkoxyethinyl 1 hydroxy 2methallyl 2,4b dimethyl 4- keto 7 lower alkylenedioxy1,2,3,4,4a,4b,5,6,7,8,10, 10a dodecahydrophenanthrene with a dilutemineral acid solution to form 1-carboalkoxymethylene-Zmethallyl-2,

4b --dimethyl 4 keto 7 lower alkylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene.

2. The process which comprises reacting l-ethoxyethinyl 1 hydroxy 2methallyl 2,4b dimethyl- 4 keto 7 ethylene dioxy1,2,3,4,4a,4b,5,6,7,8,10,

10a-dodecahydrophenanthrene with a dilute aqueous sulfuric acid in amedium comprising tetrahydrofuran to form 1 carboethoxymethylene 2methallyl 2,4b-

,dimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,

5,6,7,8,10,lOa-dodecahydrophenanthrene.

3. The process which comprises reacting l-alkoxyethinyl 1 hydroxy 2allyl 2,4b dimethyl 4 keto- .phenanthrene.

10. A compound having the'following formula:

wherein Z stands for lower alkylenedioxy; R is selected =CHCOOR from thegroup consisting of hydrogen and lower alkyl;

and Y is selected from the group consisting of allyl and methallyl.

No references cited.

10. A COMPOUND HAVING THE FOLLOWING FORMULA: